EGCG and Down syndrome

Epigallocatechin gallate (EGCG) is a green flavonol. Both studies in animal models and subsequent ones in human beings have shown that this molecule is capable of inhibiting the action of a protein called Dyrk1A produced in excess in Down syndrome on account of the triple presence of the DYRK1A gene in the chromosome 21. This excess is detrimental to brain function.

The research teams headed by Dr. de la Torre, from the IMIM and Dr. Dierssen, from the Centre of Genomic Regulation (CRG) carried out two clinical trials in young adults with Down syndrome. This pioneer research has proved the efficacy and safety of EGCG in an adult population with Down syndrome in cognitive enhancement. Furthermore, the synergy between the combination of EGCG treatment and a cognitive stimulation protocol was observed. Because many green tea extracts marketed have very low or variable EGCG concentrations, in both trials a green tea extract with a standard quantity of EGCG was used.

Initial pilot study with 30 people with DS of 14-30 years of age lasting 3 months. Half of the subjects were treated with a green tea extract with a standard quantity of EGCG (9 mg/kg/day) according to weight and the other half with placebo, in a double-blind design (neither the individuals nor the investigators knew who belonged to each group) with random assignment of the treatments. The purpose of this study was to confirm the safety and tolerability of EGCG and to obtain a certain initial evidence of the efficacy of the treatment1

1- De la Torre, R. et al., 2013. Epigallocatechin-3-gallate, a DYRK1A inhibitor, rescues cognitive deficits in Down syndrome mouse models and in humans. Molecular Nutrition & Food Research, 58(2), pp.278–288. Available in: http://doi.wiley.com/10.1002/mnfr.201300325

In a second double-blind study in which 87 people with DS between 16-34 years of age, the efficacy of the treatment over 12 months was investigated. After that period a follow-up of the participants in the study was carried out over a further 6-month post-treatment period. In all, the study lasted 18 months. The procedure consisted of the administration of EGCG (between 600-800 mg/day depending on weight) combined with a standard cognitive stimulation protocol. This treatment was compared with the administration of a placebo combined with the same cognitive stimulation protocol. 1

1- De la Torre et al. ‘Safety and efficacy of cognitive training plus epigallocatechin-¬3-¬gallate for cognitive improvement in young adults with Down syndrome (TESDAD): a double-¬blind, randomised controlled phase 2 trial”. Lancet Neurology. 6 June 2016. http://dx.doi.org/10.1016/S1474-4422(16)30034-5 http://www.ordesa.es/fontactiv/pdf/Tesdad_resumen_ejecutivo.pdf

Effects of the combination of EGCG and cognitive stimulation

The combination of EGCG with cognitive stimulation promoted significant changes in certain areas of the memory, executive functions and competences in everyday life in the participants in the study. The results suggest that the changes observed persist over at least six months after discontinuing the treatment.

Aspects relating to cognitive stimulation in the treatment combined with EGCG

Aspects relating to the safety of the treatment

EGCG is safe and well-tolerated at the doses administered. The adverse effects observed during the study were similar to those observed in the untreated placebo group (EGCG not administered). Nevertheless, EGCG is an active molecule, so adverse effects may appear as in any pharmacological treatment. It is therefore recommendable to consult the doctor so that he may assess whether they are connected with the treatment and, in this case, whether it should be discontinued.

There are two aspects relating to the thyroid and hepatic functions to be considered when starting the treatment.

– Thyroid function: During the second study it was observed that some subjects presented a slight increase in TSH values during the first months of treatment. This increase was transitory, as the values reverted to the basal value after 6 months treatment. For this reason, since hypothyroidism is very common in this group, it is recommended to perform analyses three months after starting the treatment and then a yearly follow-up.

– Hepatic function: Several parameters were analysed, such as hepatic enzymes and other biochemical parameters. Globally, no changes have been observed in hepatic functionality. However, in view of the possibility of some alteration being observed at an individual level, it is recommended to perform analyses three months after starting the treatment and then a yearly follow-up.

Aspects relating to EGCG bioavailability and dosage

The recommended dose of EGCG is 600 mg/day for a weight range between 50-75 Kg and 800 mg/day for weights ranging between 75-100 kg. These daily doses have been administered to young adults over 16 years old. The most suitable dosage has not yet been evaluated in the paediatric and adolescent population. It is recommended to consume the EGCG in a fed state.

As mentioned above, the studies were carried out with a standard green tea extract with regard to its EGCG content. The quality of green tea extract preparations is extremely variable. The green tea extracts used should have either their EGCG content clearly defined or just contain EGCG.

Aspects relating to prescription and monitoring of the efficacy and tolerability of the treatment

Before initiating the treatment with EGCG, it is recommended to consult the primary care centre doctor. He or she should prescribe the treatment and monitor it for its safety and tolerance. It is uncertain how long the treatment should last. The researchers recommend continuing it as long as therapeutic effects are observed.

Since the treatment is aimed to improve cognitive performance and behavioural functionality, it is recommended that a clinical neuropsychologist should be the one to evaluate the efficacy of the treatment. So far the treatment has been evaluated in a population between 16-34 years of age. It is therefore only recommendable from the age of 16 years onwards.1

1-. Resumen Ejecutivo del estudio TESDAD 2015: “Efecto de la combinación de la epigalocatequina galato (EGCG) y un protocolo estandarizado de estimulación cognitiva sobre funciones cognitivas y competencias en la vida diaria de adultos jóvenes con Síndrome de Down” Disponible en: http://www.ordesa.es/fontactiv/pdf/Tesdad_resumen_ejecutivo.pdf

The treatment proposed consists of the combination of EGCG with a cognitive stimulation protocol. The results of the second study suggest that the interaction between both treatments is a good therapeutic option for improving cognitive function in people with DS. The cognitive stimulation protocol used was FesKits (www.feskits.com), an integrated cognitive stimulation computer program, and validated for people with Down syndrome. There are, however, other cognitive stimulation options that are offered by the different DS institutions.

Feskits is an online cognitive stimulation method through an interactive platform. The main purposes are to improve and maintain the cognitive capacities, guided and supervised by a specialist. The treatments are elaborated by experts and have been validated in the TESDAD study for people with Down syndrome. The sessions are focused on an integral approach, stimulating all the cognitive functions in different degrees, oriented at memory training, executive training (mental flexibility, inhibitory control..) language and visual perceptive capabilities. The Feskits treatments are adapted to each individual in accordance with the execution level demonstrated at each skill outset. The program includes support mechanisms to the user’s answers, which guide and give information about his or her performance as scored in each activity.